The Maslah Saul Professor in the Department of Neurology and Professor, by courtesy, of Neurosurgery at the Stanford University Medical Center

Neurology & Neurological Sciences

Bio

Bio

Dr. Fisher is Maslah Saul MD Professor and Director of the Stanford Epilepsy Center. He had research awards from the Klingenstein Foundation, EF, CURE and NIH. He published 160 peer-reviewed articles and 4 books. He was named 1996-2016 in Best Doctors in America. He received the Ambassador Award from the International League Against Epilepsy, the 2005 AES Service Award and the 2006 Annual Clinical Research Award. Dr. Fisher is Past-President of the American Epilepsy Society, and has served on the Board of the ILAE and as Editor-in-Chief of the Journal, Epilepsia. He is past Editor-in-Chief of the website epilepsy.com. His research is on new devices to treat epilepsy.

Links

Research & Scholarship

Current Research and Scholarly Interests

Dr. Fisher is interested in clincal, laboratory and translational aspects of epilepsy research. Prior work has included: electrical deep brain stimulation for epilepsy, studied in laboratory models and clinical trials; drug delivery directly to a seizure focus in the brain; mechanisms of absence (petit mal) epilepsy and how the physiology and chemistry of brain changes in this disorder; hyperthermic (high-temperature) seizures; diagnosis and treatment of non-epileptic seizures, the post-ictal state (the condition in the aftermath of a seizure); driving and epilepsy; new antiepileptic drugs; surgery for epilepsy.

Clinical Trials

Lactic Acidosis During and After SeizuresNot Recruiting

This project looks at the time course of lactic acid rise (if any) after seizures. Salivary
and capillary lactic acid are tested. This type of measurement may be useful in signalling
the occurrence or recent history of a seizure.

The investigators are developing a questionnaire that can quickly measure the impact that
epilepsy has on a person's life. This questionnaire will be useful in following whether the
impact of epilepsy increases, decreases or stays the same over time. The results also may
point out areas that would benefit from discussion or attention in visits with your doctor.

SANTE - Stimulation of the Anterior Nucleus of the Thalamus for EpilepsyNot Recruiting

The purpose of this research is to study the safety and effectiveness of bilateral
stimulation of the anterior nucleus of the thalamus as adjunctive therapy for reducing the
frequency of seizures in adults diagnosed with epilepsy characterized by partial-onset
seizures, with or without secondary generalization, that are refractory to antiepileptic
medications.

The goal of the present clinical trial is to determine whether low frequency (0.5 Hz) rTMS
can induce long term depression in epileptogenic cortex and thus suppress cortical
excitability at the epileptic focus.

Publications

All Publications

The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know?EPILEPTIC DISORDERSBrodie, M. J., Zuberi, S. M., Scheffer, I. E., Fisher, R. S.2018; 20 (2): 77–87

Abstract

The International League against Epilepsy (ILAE) published in the April 2017 edition of Epilepsia three companion articles on the classification of seizures and the epilepsies. These represent a long-awaited update on the original 1981 and 1989 publications and provide a modern descriptive template. The new classification presents three levels of terminology, involving seizure types, epilepsy types, and syndromes. In this fourth paper, we present an interpretation of these new concepts for people with epilepsy and those who care for them, as well as for young medical doctors not specialized in epilepsy and nurses. Our goal in writing this paper is to ensure that everyone is speaking and understanding the same language, which is fundamental to the optimal management of people with epilepsy.

Abstract

The definition of who has epilepsy, classification of seizure types, and types of epilepsy have all recently been revised. The classical definition of epilepsy as a person having two or more unprovoked seizures more than 24hours apart has been expanded also to include those with one seizure and a high likelihood (more than 60%) of having another. In the new definition, epilepsy is considered to be resolved when a person is seizure-free for 10years, the terminal 5 being off seizure medicines, or when an age-dependent syndrome has been outgrown. The new seizure type classification revises the 1981 system but maintains the primary distinction of focal- versus generalized-onset seizures. Seizures also can be of unknown onset. Focal seizures may demonstrate retention or impairment of awareness, resulting in focal-aware or focal-impaired awareness seizures. Several new focal and generalized seizure types are introduced. Classification of the epilepsies is now by grouping of seizure types, etiologies, comorbidities, and epilepsy syndromes. The goal of the new terminology is greater clarity of communication and more accurate grouping of seizure types for research. Neurodiagnostic technologists can be of great help in observing clinical and electrographic features that will define the type of seizure.

Abstract

We demonstrate feasibility of using high-density EEG to map a neocortical seizure focus in conjunction with delivery of magnetic therapy. Our patient had refractory seizures affecting the left leg. A five-day course of placebo stimulation followed a month later by active rTMS was directed to the mapped seizure dipole. Active rTMS resulted in reduced EEG spiking, and shortening of seizure duration compared to placebo. Seizure frequency, however, improved similarly in both placebo and active treatment stages. rTMS-evoked EEG potentials demonstrated that a negative peak at 40 ms - believed to represent GABAergic inhibition - was enhanced by stimulation.

The New Classification of Seizures by the International League Against Epilepsy 2017CURRENT NEUROLOGY AND NEUROSCIENCE REPORTSFisher, R. S.2017; 17 (6)

Abstract

This review presents the newly developed International League Against Epilepsy (ILAE) 2017 classification of seizure types.The fundamental distinction is between seizures that begin focally in one hemisphere of the brain, generalized onset seizures that apparently originate in both hemispheres, and seizures of unknown onset. Focal seizures optionally can be subclassified according to whether awareness (a surrogate marker for consciousness) is intact or impaired. The next level of classification for focal seizures is motor (with subgroups automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic), non-motor (with subgroups autonomic, behavior arrest, cognitive, emotional, sensory), and focal to bilateral tonic-clonic. Generalized seizures are categorized as motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) and non-motor/absence (typical, atypical, myoclonic, eyelid myoclonia). The classification allows new types of focal seizures and a few new generalized seizures, and clarifies terms used to name seizures.

Abstract

This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.

Abstract

The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.

Abstract

Bilateral deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces seizures and is relatively safe but may be accompanied by complaints of memory problems and depression. This study examined incidence of memory and depression adverse events (AE) in the SANTE study blinded phase and their relationship to objective neurobehavioral measures, baseline characteristics, quality of life and long-term neurobehavioral outcome.The neurobehavioral AE and neuropsychological data from a previously reported prospective randomized trial (SANTE) were analyzed. Reliable change indices (RCI) were calculated for memory and mood measures. Analyses examined relationships among AEs, RCIs, demographic and seizure variables, and long-term neurobehavioral outcome.No significant cognitive declines or worsening of depression scores were observed through the blinded phase or in open-label at 7-years. Higher scores were observed at 7 years on measures of executive functions and attention. Depression and memory-related AEs were not associated with reliable change on objective measures or 7-year neurobehavioral outcome. The AEs were without significant impact on life quality. Memory and depression AEs were not related to demographic or seizure characteristics, change in seizure frequency, frequency of AE or depression report.Bilateral ANT DBS was associated with subjective depression and memory AEs during the blinded phase in a minority of patients that were not accompanied by objective, long-term neurobehavioral worsening. Monitoring and neuropsychological assessment of depression and memory are recommended from a theoretical standpoint and because more memory and depression AEs occurred in the active stimulation than control group.

Abstract

Clinical management of epilepsy and current epilepsy therapy trials rely on paper or electronic diaries often with inaccurate self-reported seizure frequency as the primary outcome. This is the first study addressing the feasibility of detecting and recording generalized tonic-clonic seizures (GTCS) through a biosensor linked to an online seizure database.A prospective trial was conducted with video-EEG (vEEG) in an epilepsy monitoring unit. Patients wore a wristwatch accelerometer that detected shaking and transmitted events via Bluetooth® to a bedside electronic tablet and then via Wi-Fi to an online portal. The watch recorded the date, time, audio, duration, frequency and amplitude of events. Events logged by the watch and recorded in a bedside paper diary were measured against vEEG, the "gold standard."Thirty patients were enrolled and 62 seizures were recorded on vEEG: 31 convulsive and 31 non-convulsive. Twelve patients had a total of 31 convulsive seizures, and of those, 10 patients had 13 GTCS. The watch captured 12/13 (92.3%) GTCS. Watch audio recordings were consistent with seizures in 11/12 (91.6%). Data were successfully transferred to the bedside tablet in 11/12 (91.6%), and to the online database in 10/12 (83.3%) GTCS. The watch recorded 81 false positives, of which 42/81 (51%) were cancelled by the patients. Patients and caregivers verbally reported 15/62 seizures (24.2% sensitivity) but no seizures were recorded on paper logs.Automatic detection and recording of GTCS to an online database is feasible and may be more informative than seizure logging in a paper diary.

Abstract

Counting seizures is not simple. Patients may not be aware of their seizures. Adherence to diary entry often is poor. Shake detectors pick up only seizures with rhythmic movements and suffer from false-positive results. Measurement of electrodermal response is a promising technology but sensitivity and specificity for partial seizures are uncertain. Video-electroencephalogram monitoring is accurate but of short duration and performed in an artificial and expensive environment. Invasive electroencephalogram electrodes can detect seizure-like patterns, sometimes of unknown clinical significance. Practical long-term electroencephalogram monitors are under development. Methods to rank seizure severity are subjective. New approaches and solutions are needed.

Abstract

The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes.The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events.Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3).The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

Abstract

Electrical stimulation of the septal nuclei via deep brain stimulating electrodes is proposed as a potentially beneficial therapy for medication-resistant temporal lobe epilepsy. In a multicenter study, stimulation of anterior thalamus was shown to reduce numbers of seizures, but decrease was only in the range of 40%. This might be improved with septal stimulation, which has strong and direct reciprocal connections with the hippocampal formation, the structure most involved in temporal lobe epilepsy. Medial septal neurons drive a 3-12Hz theta rhythm in hippocampus of rodents. Theta rhythm is less obvious in human hippocampus, but it is present and it varies with cognitive tasks. The hippocampal theta rhythm is disrupted by seizures. In animal models, restoration of theta by sensory stimulation, septal electrical stimulation or cholinergic drugs infused into septum ameliorates seizures. Seizure activity in hippocampus is faithfully reflected in septal nuclei, and septum sometimes leads the seizure activity. A subset of patients with temporal lobe epilepsy have structural enlargement of their septal nuclei. At high levels of intensity, septal stimulation is subjectively pleasurable and strongly reinforcing. Rats will repeatedly press a bar to stimulate their septum. Initial experience with human septal stimulation in the 1950s was not favorable, with ineffective therapy for schizophrenia and a high rate of surgical complications. Subsequent experience in 50-100 pain patients employing modern neurosurgical techniques was more favorable and demonstrated septal stimulation to be safe and tolerable. The current state of knowledge is sufficient to consider design of a clinical trial of medial septal stimulation in selected patients with medication-resistant temporal lobe epilepsy.

Abstract

Little is known about patterns of seizures that occur multiple times a day, sometimes called clusters or serial seizures.The online diary, My Epilepsy Diary (MED), provided self-reported data from community-based patients to describe the characteristics of clusters.We used MED data to define a population of 5098 community outpatients, including 1177 who specified time of multiple seizures in a 24-hour period. Outcomes included cluster prevalence and frequency, distribution of interseizure time intervals, as well as the types of triggers commonly reported.One-fourth of days with any seizures included clusters for these patients. Most days with clusters included 2 seizures, with >5 events occurring in only 10% of days. One-third of seizures occurred within 3h of the initial event and two-thirds within 6h. When more than 2 seizures occurred, the time to the next seizure decreased from an average of over 2h (to the 3rd event) to a quarter-hour (from the 4th to the 5th event).My Epilepsy Diary data have provided the first overview of cluster seizures in a large community-based population. Treatments with less than 3-hour duration of action would be bioavailable at the time of only one-third of subsequent seizures. Although limited by the self-reported and observational nature of the diary data, some general patterns emerge and can help to focus questions for future studies.

Abstract

In 2014, the definition of epilepsy was revised by the International League Against Epilepsy (ILAE).A conceptual definition of epilepsy was proposed by the ILAE in 2005, as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by its psychosocial consequences. Practical application of the epilepsy definition usually is taken to mean at least two unprovoked seizures more than 24 h apart, but a 2014 practical definition refines the description. With this definition, epilepsy is a disease of the brain with either: (1) at least two unprovoked (or reflex) seizures occurring more than 24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals past the applicable age of an age-dependent epilepsy syndrome or those who have remained seizure-free for the past 10 years, with no seizure medicines for the past 5 years.A consensus process has refined the definition of epilepsy.

Abstract

To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy.This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.

Abstract

Electroencephalography is useful for evaluating transient neurological events in the setting of moyamoya disease.EEG findings of adults with moyamoya seen at a large moyamoya referral center are summarized. Patients were identified by retrospective chart review.EEGs were ordered after cerebral revascularization for altered mental status, aphasia, limb shaking, or facial twitching. Among the study population of 103 patients having EEGs, 24% of adults with moyamoya had a history of clinical seizures. Ischemic or hemorrhagic strokes were associated with a twofold relative risk of seizures. Overall, 90% of EEGs were abnormal, most commonly focally (78%), or diffusely slow (68%). Epileptiform EEG discharges were seen in 24%. Whereas hemispheres with an ischemic stroke had a 19% risk of epileptiform discharges and an 8% risk of seizures on EEG, hemispheres with hemorrhagic stroke had a 35% risk of epileptiform discharges and 19% risk of seizures on EEG. Focal amplitude attenuation was seen in 19%, breach rhythm in 15%, rhythmic delta in 14%, and electrographic seizures in 12%.Seizures and epileptiform EEG changes are common in patients with moyamoya disease.Transient events in patients with moyamoya can result from seizures as well as ischemia.

Abstract

Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

Abstract

Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0-89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15-67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.

Abstract

The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains.Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21-71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE-31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test-retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed.The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0-4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE-31.The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change.

Abstract

Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients. Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (e.g., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection. We reviewed 34 articles that reported the prevalence of ictal tachycardia in patients with epilepsy. Scientific literature supports the occurrence of significant increases in heart rate associated with ictal events in a large proportion of patients with epilepsy (82%) using concurrent electroencephalogram (EEG) and electrocardiogram (ECG). The average percentage of seizures associated with significant heart rate changes was similar for generalized (64%) and partial onset seizures (71%). Intra-individual variability was noted in several articles, with the majority of studies reporting significant increase in heart rate during seizures originating from the temporal lobe. Accurate detection of seizures is likely to require an adjustable threshold given the variability in the magnitude of heart rate changes associated with seizures within and across patients.

Abstract

Neurostimulation enables adjustable and reversible modulation of disease symptoms, including those of epilepsy. Two types of brain neuromodulation, comprising anterior thalamic deep brain stimulation and responsive neurostimulation at seizure foci, are supported by Class I evidence of effectiveness, and many other sites in the brain have been targeted in small trials of neurostimulation therapy for seizures. Animal studies have mainly assisted in the identification of potential neurostimulation sites and parameters, but much of the clinical work is only loosely based on fundamental principles derived from the laboratory, and the mechanisms by which brain neurostimulation reduces seizures remain poorly understood. The benefits of stimulation tend to increase over time, with maximal effect seen typically 1-2 years after implantation. Typical reductions of seizure frequency are approximately 40% acutely, and 50-69% after several years. Seizure intensity might also be reduced. Complications from brain neurostimulation are mainly associated with the implantation procedure and hardware, including stimulation-related paraesthesias, stimulation-site infections, electrode mistargeting and, in some patients, triggered seizures or even status epilepticus. Further preclinical and clinical experience with brain stimulation surgery should lead to improved outcomes by increasing our understanding of the optimal surgical candidates, sites and parameters.

Abstract

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

How Can We Identify Ictal and Interictal Abnormal Activity?Workshop on Issues in Clinical Epileptology - A View from the Bench held in honor of PhilFisher, R. S., Scharfman, H. E., deCurtis, M.SPRINGER.2014: 3–23

Abstract

The International League Against Epilepsy (ILAE) defined a seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain." This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word 'seizure,' such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise.

Abstract

Deep brain stimulation for seizures has been applied to cerebellum, caudate, locus coeruleus, subthalamic nucleus, mammillary bodies, centromedian thalamus, anterior nucleus of thalamus, hippocampus and amygdala, hippocampal commissure, corpus callosum, neocortex, and occasionally to other sites. Animal and clinical studies have primarily investigated seizure prevention and, to a lessersmaller extent, seizure interruption. No studies have yet shown stimulation able to cure epilepsy. A wide variety of stimulation parameters have been employed in multiple different combinations of frequencies, amplitudes, and durations. Literature review identifies at least 52 clinical studies of brain stimulation for epilepsy in 817 patients. Two studies were large, randomized, and controlled, one in the anterior nucleus of thalamus and another at the cortical or hippocampal seizure focus; both of these studies showed efficacy and tolerability of stimulation. Many questions remain. We do not know the mechanisms, the best stimulation parameters, the best patient population, or how to predict benefit in advance. We do not know why benefit of neurostimulation for epilepsy seems to increase over time or whether there are long-term deleterious effects. All of these questions may be answerable with a combination of laboratory research and clinical experience.

Abstract

An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials.This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries.Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by epilepsy.com and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries. Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data. Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a "real-world" environment. Diary-based studies can also be useful as descriptive "snapshots" of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication. Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious.Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials.

Abstract

Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.Receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ∞; 95% CI, 11.8 to ∞; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution.clinicaltrials.gov Identifier: NCT00040326.

Abstract

Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation (VNS), which continues to develop new technology, is approved for use in the United States. Deep brain stimulation of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to 1 or 2 seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS are split on efficacy, which may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of shake detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of electroencephalography (EEG) is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures, and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience.

Abstract

My Epilepsy Diary is a free Web-based application on the public website epilepsy.com, available for patients to track epilepsy and to aid clinicians with data-based, individualized management. The first aim of this descriptive study was to outline electronic diary functions. Second, the study retrospectively profiled a large cohort of 2010 calendar year diary users including demographics, seizure types, temporal distribution of seizures, triggers, and use and side effects of antiepileptic drugs (AEDs). A total of 1944 users provided demographic information and 1877 recorded seizure data. Most (64%) users were women. Average age was 29.9±16.0 years. A total of 70,990 seizure entries and 15,630 AED entries were logged. Events were apportioned as 79% seizures and 21% seizure clusters. Specific AEDs were detailed in 7331 entries: monotherapy was used in 18% and polytherapy in 82%. Mood-related side effects were most commonly reported in 19% of 1027 users.

Abstract

Caregivers of people with epilepsy are commonly concerned about unwitnessed seizures causing injury and even death. The goal of this study was to determine if a wrist-worn motion detector could detect tonic-clonic seizures. Individuals admitted for continuous video/EEG monitoring wore a wristwatch-size device that was programmed to detect rhythmic movements such as those that occur during tonic-clonic seizures. When such movement was detected, the device sent a Bluetooth signal to a computer that registered the time and duration of the movements. Recorded detections were compared with the routinely recorded video/EEG data. Six of 40 patients had a total of eight tonic-clonic seizures. Seven of the eight seizures were detected. Nonseizure movements were detected 204 times, with opportunity for canceling transmission by the patient. Only one false detection occurred during sleep. In principle, this device should allow caregivers of people with tonic-clonic seizures to be alerted when a seizure occurs.

Abstract

The postictal state is the abnormal condition occurring between the end of an epileptic seizure and return to baseline condition. Applying this definition operationally can be difficult, especially for complex partial seizures, where cognitive and sensorimotor impairments merge imperceptibly into the postictal state. Many patients are unaware of even having had a seizure. Electroencephalography sometimes helps to distinguish ictal from postictal periods, but may demonstrate focal slowing both during and after a seizure. Epileptiform electroencephalographic changes do not always correspond precisely to behavioral changes, especially with scalp recordings. The postictal state ends at the interictal state, but this too can be ambiguous. Interictal spikes and spike-waves can be associated with cognitive and behavioral impairments, suggesting that they may represent fragments of ictal episodes. Except where boundaries are clear, it is better to describe a sequence of behaviors and electroencephalographic changes, without labeling arbitrary stages as being ictal or postictal.

Abstract

High altitude headache (HAH) is the most common neurological complaint at altitude and the defining component of acute mountain sickness (AMS). However, there is a paucity of literature concerning its prevention. Toward this end, we initiated a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya designed to compare the effectiveness of ibuprofen and acetazolamide for the prevention of HAH.Three hundred forty-three healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. Outcome measures included headache incidence and severity, AMS incidence and severity on the Lake Louise AMS Questionnaire (LLQ), and visual analog scale (VAS).Two hundred sixty-five of 343 subjects completed the trial. HAH incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%; P = .95), and both agents were significantly more effective than placebo (45.3%; P = .01). AMS incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%; P = .34), and both agents were significantly more effective than placebo (28.6%; P = .03). In fully compliant participants, moderate or severe headache incidence was similar when treated with acetazolamide (3.8%) or ibuprofen (4.7%; P = .79), and both agents were significantly more effective than placebo (13.5%; P = .03).Ibuprofen and acetazolamide were similarly effective in preventing HAH. Ibuprofen was similar to acetazolamide in preventing symptoms of AMS, an interesting finding that implies a potentially new approach to prevention of cerebral forms of acute altitude illness.

Abstract

We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Abstract

Objective. Motor cortex stimulation (MCS) is increasingly being utilized for the treatment of intractable pain. While the risks of MCS are relatively low, focal or generalized seizures may be produced during programming of MCS systems. Occasionally, patients may experience seizures hours after programming. In order to understand this phenomenon better, we undertook a retrospective analysis of five patients in whom seizures limited the efficacy of MCS. Methods. A retrospective chart review was performed in five patients who underwent MCS between 2002 and 2006 and who had persistent seizures that limited programming. Results. The initial seizure during programming in these patients occurred at amplitudes of between 4.8 and 6.6 V. Four patients experienced generalized tonic-clonic seizures and one patient experienced focal seizures. Subsequent seizures occurred at amplitudes of between 4.4 and 5.5 V, with a tendency for seizure thresholds to progressively decrease. All five patients experienced at least one seizure occurring many minutes to hours after programming, with no side-effects initially observed once the final settings had been programmed. Four out of five patients were programmed with frequencies documented at between 70 and 90 Hz; documentation on frequency was unavailable for the remaining patient. One patient never achieved adequate pain relief and had the MCS system explanted. Conclusions. Despite the overall safety of MCS for the treatment of chronic pain, seizures during and after programming are a serious risk that should be anticipated. In this group of patients, seizures were associated only with stimulus rates between 70 and 90 Hz. No patient developed chronic epilepsy from the stimulation.

Abstract

DBS has been a possible therapy for epilepsy for more than 30 years, and now it is moving to the point of clinical utility. Animal models have shown efficacy of DBS at several brain regions, although not all animal studies have shown efficacy. Clinically, an array of sites have been explored, including the cerebellum, anterior nucleus of the thalamus, CM nucleus, hippocampus, subthalamic nucleus, brainstem, and corpus callosum; direct stimulation of the cortex has also been explored. Interest in evaluating these sites for treatment of epilepsy has been enhanced by the success of vagus nerve stimulation for epilepsy and DBS for movement disorders. Literature consists of mostly small and uncontrolled studies that are subject to limitations in interpretation. A pivotal large, double-blind controlled trial of anterior nucleus of the thalamus has recently been completed, and it showed efficacy for partial seizures with or without secondary generalization.28 A controlled trial for RNS is underway.57 In addition, pilot studies of hippocampal stimulation 41,43 are expected to lead to more definitive trials of this site.Brain stimulation for epilepsy holds several challenges for the future. Mechanisms of DBS are poorly understood, although investigations are actively being pursued. Little is known about optimal stimulation parameters. DBS has been little examined in cases of intractable generalized epilepsy. Because DBS carries some risk, mainly of hemorrhage and infection, clinicians will need to develop an effective method of identifying the best candidates. DBS is palliative rather than curative, but experience suggests that this relatively new therapy may be of benefit to some people with otherwise untreatable epilepsy.

Abstract

Great advances have been made in the diagnosis of people with psychogenic nonepileptic seizures (PNES) since the advent of video/EEG monitoring. However, treatment options for this population have lagged significantly. This pilot study was undertaken to evaluate whether group therapy done with a psychodynamic focus would offer a useful intervention. Twelve patients entered the study and seven completed at least 75% of the 32 weekly sessions. The Beck Depression Inventory and the Global Severity Index of the Symptom Checklist-90 showed improvement as well as an overall decrease in PNES frequency. The data suggest that group therapy focusing on interpersonal issues may benefit patients with PNES.

Abstract

We examined the usefulness of video versus EEG in isolation for the differentiation of epileptic seizures (ES) from psychogenic nonepileptic events (PNEE). Video-EEG recordings of 43 events in 43 patients (27 with ES and 16 with PNEE) were analyzed by experienced clinical epileptologists/electroencephalographers blinded to the patients' clinical histories. Both the video and EEG were scored independently by the same reader for each event. Relying on video recordings alone, the readers correctly identified ES with a sensitivity of 93% and specificity of 94%. Based on EEG data alone, the readers correctly identified ES with a sensitivity of 89% and specificity of 94%. Semiologically, a gradual evolving buildup of visible symptoms, reaching maximal behavioral intensity within 70 seconds of event onset, was a reliable indicator of ES. No patient with ES demonstrated eye closure at the time of peak behavioral manifestations. Although several additional semiologic features were statistically associated with either ES or PNEE, they were less reliably present and, hence, less clinically useful. Correct categorization of some neurobehavioral events can be made by experienced epileptologists on the basis of video or EEG recordings during an event, without simultaneous review of both provided that the full event is recorded. Home video recordings may represent a useful screening tool for a subset of patients with neurobehavioral events of unclear etiology.

Abstract

Epilepsy recently has been defined conceptually as a condition of at least one seizure, with an enduring predisposition to have seizures. It is not yet clear how to make this definition operational and practical. A diagnosis of epilepsy has potentially serious consequences for health, psychosocial well-being, and economics, and, therefore, it should be made with a high level of certainty. A definite diagnosis of epilepsy can be made with two unprovoked seizures at least 24 h apart. This method has the benefit of simplicity and consistency with past epidemiologic studies. Nevertheless, certain circumstances suggest a high likelihood of having a second seizure, as evidenced by common clinical practice of considering treatment after a first unprovoked seizure in conjunction with additional risk factors (surrogate markers). One unifying approach is an operational definition of "definite epilepsy" after two unprovoked seizures at least 24 h apart. An operational definition of "probable epilepsy" can be established with one unprovoked seizure and clinical, electroencephalography (EEG), neuroimaging, genetic, or other information to suggest greater than a 50% chance of having another seizure. "Possible epilepsy" operationally would exist with a single unprovoked seizure and insufficient evidence to predict a high likelihood of recurrence. Future clinical and epidemiologic evidence would allow refinements of the operational definitions.

Abstract

Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients.

Abstract

Use of novel drug delivery methods might enhance efficacy and reduce toxicity, in comparison with currently existing oral anti-epileptic drugs (AEDs). Novel methods aim to deliver optimal drug concentration more specifically to the seizure focus or foci. In this review, we first consider unconventional routes of drug delivery to the peripheral system, then potential new methods of targeted CNS drug delivery. Intrathecal or intraventricular AEDs might circumvent systemic toxicity. Drug-eluting wafers could be surgically positioned over an epileptogenic region of brain. Drug can be delivered to a seizure focus by an implanted catheter and subcutaneous pump. Inactive prodrugs, given systemically, can be made active only at the seizure focus, by interaction with locally-released substances. Liposomes and polysomes are engineered slow-release storage vehicles for drugs. Targeting components can hold liposomes near a region of interest, provided that they can penetrate the blood brain barrier. Lastly, we discuss future prospects for the use of transplanted cells and genes as potential vehicles for local delivery of renewable anti-epileptic regimen.

Abstract

Neonatal treatment of Long-Evans Hooded rats with the cholesterol synthesis inhibitor (CSI) AY9944 has been shown to increase occurrence of spike-waves in EEG recordings and decrease benzodiazepines sensitivity of GABA(A) receptor-mediated responses in neurons from the thalamic reticular nuclei (nRt, Wu et al., 2004). The present experiments were designed to investigate the changes in the gamma2 and alpha1 subunits of the GABA(A) receptor in CSI model rats as possible mechanisms of these changes. Western blot, immunohistochemistry and real-time PCR techniques were performed to measure the levels of GABA(A) receptor gamma2 and alpha1 subunit transcripts and protein in the nRt and ventrobasal (VB) relay nuclei of thalamus and in somatosensory cortex. In CSI model animals, Western blot results showed that gamma2 subunit expression significantly decreased in thalamus (control, n=6: 0.17+/-0.02 relative to actin vs. CSI model, n=6: 0.11+/-0.01, P<0.05) but neither in cortex nor in hippocampal tissues. Conversely, alpha1 subunit expression decreased in CSI model somatosensory cortex, but not in nRt and VB. The present results demonstrate that neonatal block of cholesterol synthesis produces region- and subunit-specific decreases in GABA(A) receptor subunits in thalamus and cortex. Selective reductions in GABA(A) receptor subunits in thalamus may play a role in pathophysiology of absence epilepsy.

Abstract

The purpose of this article is to review the use of serum prolactin assay in epileptic seizure diagnosis.The authors identified relevant studies in multiple databases and reference lists. Studies that met inclusion criteria were summarized and rated for quality of evidence, and the results were analyzed and pooled where appropriate.Most studies used a serum prolactin of at least twice baseline value as abnormal. For the differentiation of epileptic seizures from psychogenic nonepileptic seizures, one Class I and seven Class II studies showed that elevated serum prolactin was highly predictive of either generalized tonic-clonic or complex partial seizures. Pooled sensitivity was higher for generalized tonic-clonic seizures (60.0%) than for complex partial seizures (46.1%), while the pooled specificity was similar for both (approximately 96%). Data were insufficient to establish validity for simple partial seizures. Two Class II studies were consistent in showing prolactin elevation after tilt-test-induced syncope. Inconclusive data exist regarding the value of serum prolactin following status epilepticus, repetitive seizures, and neonatal seizures.Elevated serum prolactin assay, when measured in the appropriate clinical setting at 10 to 20 minutes after a suspected event, is a useful adjunct for the differentiation of generalized tonic-clonic or complex partial seizure from psychogenic nonepileptic seizure among adults and older children (Level B). Serum prolactin assay does not distinguish epileptic seizures from syncope (Level B). The use of serum PRL assay has not been established in the evaluation of status epilepticus, repetitive seizures, and neonatal seizures (Level U).

Abstract

The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have come to consensus definitions for the terms epileptic seizure and epilepsy. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.

Abstract

The production of artwork is a complex neurological task. A controlled study of artwork produced by people with epilepsy has not previously been performed. The present report details the results of a three-part study involving 60 subjects from a comprehensive epilepsy center population. Subjects were grouped by the following diagnoses: seizures, partial seizures, complex partial seizures with temporal focus, and nonepileptic events. Data were collected in a blinded fashion. The Formal Elements Art Therapy Scale task showed significant effects in patients with epileptic seizures. The Free Drawing was most sensitive to complex partial seizures with temporal focus, while the Outline was most predictive of nonepileptic events. In addition to giving some insight into the neurological functioning of these subjects, this pilot study provides a basis for the future development of diagnostic tests to be used within this patient group.

Abstract

Electrical stimulation of the nervous system is an attractive possible therapy for intractable epilepsy, but only stimulation of the vagus nerve has been subjected to large, controlled, and completed clinical trials. Controlled trials are in progress for intermittent cycling stimulation of the anterior nuclei of the thalamus, and for cortical stimulation at a seizure focus, responsive to detection of seizure onset. Anecdotal experience has been gathered with stimulation of cerebellum, centromedian thalamus, subthalamus, caudate, hippocampus, and brainstem. All stimulation of the central nervous system for epilepsy must be considered experimental.

Abstract

Prophylactic drug injection directly onto a seizure focus has the potential to improve seizure control with fewer side effects than is produced by systemic therapy. Using a dose-response model, we evaluated the effectiveness of adenosine application for focal seizure prophylaxis in 12 rats. Total spikes and electroencephalographic ictal events were reduced significantly by treatment with adenosine compared to control (P < 0.0001). This study demonstrates effectiveness and feasibility in a model system using intracranial injection of adenosine to prevent epileptiform events.

Abstract

Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI model, and suggest that decreased gamma2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.

Abstract

Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data.We report an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline.Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters.Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.

Abstract

We developed a screening methodology to test the ability of putative antiepileptic drugs delivered directly to a seizure focus to prevent epileptiform activity. The left hippocampi of 15 rats were implanted with an injection cannula and bipolar recording electrodes. Bone screws were used to record neocortical EEG activity. Diazepam (DZP) at one of four possible concentrations or control solution was injected into the hippocampus, followed 5 min later by bicuculline methiodide. DZP suppressed spikes and ictal events in a dose-dependent manner (P<0.0001). At 100 mM, DZP reduced spikes from 678+/-128 to 87+/-35 for a 15 min segment. Numbers of ictal events (seizure) and latency to the first event were reduced by prophylactic DZP. The study establishes a protocol for testing of intracranially-injected drugs to prevent focal seizures.

Abstract

Neural stimulation is a promising new technology for the treatment of medically-intractable seizures. Vagus-nerve stimulation (VNS) is licensed in several countries as an adjunctive therapy. VNS is as effective as antiepileptic drug therapy, and serious complications are rare. Transcranial magnetic stimulation is simple, non-invasive, and widely used in neurophysiology. Therapeutic results in a few studies are equivocal at best. Deep brain stimulation, although experimental, has been applied to the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, hippocampus, and neocortical seizure foci. Preliminary results are encouraging, but not conclusive. Electrode implantation in the brain for indications other than seizures has been associated with a 5% risk for intracranial haemorrhage and 5% for infection. A controlled study of anterior thalamic stimulation in patients with intractable partial and secondarily generalised seizures has been started. Future investigations are likely to study extrathalamic sites of stimulation, and effects of stimulation contingent upon detection of or prediction of EEG patterns of epileptiform activity.

Abstract

To evaluate whether changing the seizure-free interval in Arizona from 12 months to 3 months affected the number of seizure-related motor vehicle crashes.We performed a time trend study with analysis of motor vehicle crash reports in the state of Arizona 3 years before (1991-1993) and 3 years after (1994-1996) the seizure-free interval was decreased from 12 to 3 months. The number of motor vehicle crashes related to seizures, other medical conditions, and other nonmedical crashes was compared before and after the law changed. Other population trends, including population growth, registered vehicles, and registered drivers, are also reported.Seizure-related crashes increased from 125 to 136 for the 3 years before and 3 years after the law changed, respectively. The total rate of seizure-related crashes did not increase on the basis of an incidence rate difference of -0.03/10(9) miles (95% confidence interval [CI], -0.30 to 0.24) and a relative risk of 0.98 (95% CI, 0.77 to 1.24). Over the same time interval, crashes related to other medical conditions increased from 288 to 310, respectively, for an incidence rate difference of -0.09/10(9) miles (95% CI, -0.51 to 033) and a relative risk of 0.97 (95% CI, 0.82 to 1.13). Fatalities due to seizure-related crashes decreased during the same period, whereas the number of multiple vehicle crashes increased.The rate of seizure-related crashes did not significantly increase in the state of Arizona after the seizure-free interval was reduced from 12 to 3 months.

Abstract

Nonepileptic seizures (NES) are frequently thought to have a "psychogenic" basis. Two 6-month group psychotherapy programs were provided for patients diagnosed as having NES [eight patients were treated during the first program, seven during the second (N=15)] to explore the potential role of psychological factors in the genesis of NES and to determine if psychotherapeutic interventions reduced the frequency of NES. Of the 15 patients, 9 (60%) completed at least 58% of the treatment sessions. Of those 9 patients, 6 (66%) reported a decline in "seizure frequency." One reported an increase (11%). Self-reported frequency highly correlated with paranoid ideation. Dissociative phenomena were common as was a history of sexual abuse. Each patient reported being in an adult situation that they found unacceptable or intolerable. None perceived a solution to their situation. Reports by health care providers that their seizures were not "real" (i.e., true epilepsy) restimulated feelings associated with their not being believed when they reported being sexually abused as children. The psychological genesis of NES in this sample of patients appears rooted in the recurrent experience of being in abusive or exploited relationships for which they perceived no solution.

Abstract

Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated in the clinical setting. Gene therapy also may play a role in local drug delivery with the use of adenovirus, adeno-associated virus, herpesvirus or other delivery vectors to induce brain cells to produce local modulatory substances. New delivery systems should significantly improve the therapeutic/toxic ratio of AEDs.

Abstract

Recently a hyperthermic rat hippocampal slice model system has been used to investigate febrile seizure pathophysiology. Our previous data indicates that heating immature rat hippocampal slices from 34 to 41 degrees C in an interface chamber induced epileptiform-like population spikes accompanied by a spreading depression (SD). This may serve as an in vitro model of febrile seizures.In this study, we further investigate cellular mechanisms of hyperthermia-induced initial population spike activity. We hypothesized that GABA(A) receptor-mediated 30-100 Hz gamma oscillations underlie some aspects of the hyperthermic population spike activity. In 24 rat hippocampal slices, the hyperthermic population spike activity occurred at an average frequency of 45.9 +/- 14.9 Hz (Mean +/- SE, range = 21-79 Hz, n = 24), which does not differ significantly from the frequency of post-tetanic gamma oscillations (47.1 +/- 14.9 Hz, n = 34) in the same system. High intensity tetanic stimulation induces hippocampal neuronal discharges followed by a slow SD that has the magnitude and time course of the SD, which resembles hyperthermic responses. Both post-tetanic gamma oscillations and hyperthermic population spike activity can be blocked completely by a specific GABA(A) receptor blocker, bicuculline (5-20 microM). Bath-apply kynurenic acid (7 mM) blocks synaptic transmission, but fails to prevent hyperthermic population spikes, while intracellular diffusion of QX-314 (30 mM) abolishes spikes and produces a smooth depolarization in intracellular recording.These results suggest that the GABA(A) receptor-governed gamma oscillations underlie the hyperthermic population spike activity in immature hippocampal slices.

Abstract

We performed a pilot 3-month, open-label study of 5-10 mg donepezil, an anticholinesterase inhibitor, as treatment for memory problems in people with epilepsy. The Buschke Selective Reminding Test was administered at baseline and after 3 months of donepezil. In 18 completing patients, the total number of words recalled across learning trials was greater on donepezil (P = 0.4). No change was noted in attention, visual sequencing, mental flexibility, psychomotor speed, or reported quality-of-life scores. Mean 3-month seizure frequency at baseline was 2.70 ± 4.60, and during treatment, 3.06 ± 4.52 (P = 0.19, not significant). Two patients experienced increased tonic-clonic seizures. Side effects included diarrhea, stomach cramps, insomnia, depression, and blurred vision. Cholinergic medication is worthy of investigation as treatment for memory problems in people with epilepsy, but attention must be paid to possible exacerbation of seizures.

Abstract

To compare the tolerability of two different dose-initiation regimens of gabapentin for the adjunctive treatment of partial seizures.Patient compliance is a key feature of successful outpatient pharmacologic therapy for epilepsy, and one aspect of compliance is simplicity of initiation. By using a rapid titration rate, leading to a rapid therapeutic gabapentin dose, perhaps there could be an improvement with compliance.Male or female patients, at least 12 years old, with a recent history of partial seizures with or without secondary generalization, were randomized to receive gabapentin (following a blinded placebo period of an undisclosed number of days) as either a Slow initiation (300 mg day 1, 600 mg day 2, then 900 mg/day) or a Rapid initiation (900 mg/day immediately following the placebo lead-in).Starting gabapentin therapy at an initial therapeutic dosage of 900 mg/day is well tolerated by patients with epilepsy and is as safe as initiating with a titration schedule over 3 days. Of the four most common adverse events (somnolence, dizziness, ataxia, fatigue), only one, dizziness, occurred more often in the nontitrated (Rapid initiation) group than in the titrated (Slow initiation) group.Initiation of gabapentin at 900 mg/day is as well tolerated as is a 3-day titration, except for a higher incidence of dizziness.

Abstract

Febrile seizures are the most common seizure type in children (6 mo to 5 yr). The pathophysiology of febrile seizures is unknown. Current genetic studies show that some febrile seizures result from channelopathies. We have performed electrophysiological experiments in in vitro hippocampal slices to test a novel hypothesis that a disordered regulation of ionic homeostasis underlies the genesis of febrile seizures. In transverse hippocampal CA1 slices from 104 rats, temperature increase from 34 degrees to 40 degrees C produced a series of spreading depressions (SDs), called hyperthermic SDs. The hyperthermic SDs were age-dependent, occurring in only 1/17 8-16 day-old animals, 44/49 17-60 day-old animals, and 11/20 rats older than than 60 days. The hyperthermic SDs usually occurred on the rising phase of the temperature. The mean temperature to trigger a first hyperthermic SD was 38.8 +/- 1.3 degrees C (mean +/- SD, n = 44). The hyperthermic SDs induced a reversible loss of evoked synaptic potentials and a dramatic decrease of input resistance. Neuronal and field epileptiform bursting occurred in the early phases of the hyperthermic SD. During hyperthermic SDs, pyramidal cell membrane potential depolarized by 38.3 +/- 4.9 mV (n = 20), extracellular field shifted negative 18.5 +/- 3.9 mV (n = 44), and extracellular K(+) rose reversibly to 43.8 +/- 10.9 mM (n = 6). Similar SDs could be evoked by ouabain or transient hypoxia with normal temperature. Tetrodotoxin could block initial epileptiform bursting, without blocking SDs. Hyperthermia-induced SDs should be investigated as possible contributing factors to febrile seizures.

Abstract

A national survey of 1023 people with epilepsy in the US assessed their attitudes about their therapies. Subjects were drawn from responders to a previous national survey of US households or from those who phoned the Epilepsy Foundation. Overall response rate was 49%. Approximately 90% of the respondents were taking medications for their epilepsy. Only 56% were on monotherapy, while 26% were taking two, 6% three, and 2% four medications. Only 68% of respondents were very satisfied with their current seizure medications. When asked to rank five areas of importance regarding their seizure medication, the rank order (highest to lowest) was seizure control, fewer side effects, convenient dosing regimens and cost. Adverse medication events were listed in descending rank order as problems with cognition, energy level, school performance, childbearing, coordination, and sexual function. Inter-individual differences in side effects of concern were listed, suggesting medication choices should be individualized according to potential side effects. Twenty percent of 920 respondents adjusted their medications on their own, by adjusting amount (62%), dosing schedule (31%), or both (3%). Eighty percent of respondents were satisfied with their medical care systems. In this group, 82% had health insurance that covered epilepsy. The large majority (94%) of respondents had seen a neurologist. Subjects expressed dissatisfaction about time limits and lack of accessible information about epilepsy. People with epilepsy are generally satisfied with efforts to treat their disorder, but adverse events are of concern. Many patients requested more information about epilepsy.

Abstract

This study surveyed the perceptions about and subjective experience of 1023 people with epilepsy in two community-based samples: one from a national postal survey; the other callers to the Epilepsy Foundation. Response to a mail survey was 49%. In comparison with US Census Bureau norms, respondents had received less education, were less likely to be employed or married, and came from lower income households. Complex partial seizures were the most prevalent seizure type, but a convulsion had occurred in 61%. Fifty percent of respondents reported incomplete control of their seizure disorder, although 25% of these had a seizure in the prior year. Thirteen percent had a longest inter-seizure interval of a year or greater, 37% of 3 months, 22% of 1 month, 10% of 1 week and 4% of 1 day. Respondents listed uncertainty and fear of having a seizure as the worst thing about having epilepsy. Lifestyle, school, driving, and employment limits were also listed as major problems. When asked to rank a list of potential problems, cognitive impairment was ranked highest. These data indicate that ongoing medical and psychosocial problems continue for those with epilepsy in the view of those questioned and their families, even in a sample where the majority report good control of their epilepsy.

Abstract

Some of the disability deriving from epilepsy derives from the postictal state (PS). The PS may be complicated by impaired cognition, headache, injuries, or secondary medical conditions. Postictal depression is common, postictal psychosis relatively rare, but both add to the morbidity of seizures. The mechanisms of the PS are poorly understood. Alteration of cerebral blood flow both results from and contributes to the PS. Many neurotransmitters or neuromodulators are involved in the physiology of the PS. Response to glutamate may partially desensitize after a seizure. Endogenous opiates and adenosine serve as natural antiepileptic medications in some circumstances. Nitric oxide has numerous effects on brain excitability, and may be particularly important in regulating postictal cerebral blood flow. Just as the pathophysiology of seizures is complicated, so is that of the PS multifactorial. As a practical issue, it would be very useful to have medications that reduce the morbidity of the PS.

Abstract

A total of 1023 individuals with epilepsy responded to a community-based questionnaire survey. Relative to U.S. population norms, respondents had lower household incomes and lesser levels of educational and vocational attainment. Although 89% of respondents reported that their seizures were, in their estimation, at least somewhat controlled, 57% reported having suffered at least one seizure in the preceding year. Of the many concerns that accompanied life with epilepsy, fear (of a seizure, of embarrassment, even of death) was the issue most frequently reported. Eighty-eight percent of respondents reported having health insurance, and this insurance covered epilepsy treatment in 93% of cases. The majority of respondents said that they were satisfied with the medical care they were receiving but wished for more information about epilepsy. Despite advances in epilepsy therapy, freedom from seizures and optimal quality of life eludes many.

Abstract

A seizure warning device might allow some individuals with partial seizures to protect themselves against consequences of seizures, but a prerequisite is the ability to take volitional action in response to a warning. The authors reviewed consecutive seizures in their epilepsy monitoring unit to determine whether patients could squeeze an event bulb, as instructed, at the start of their seizure. Only complex partial seizures with EEG changes and with the patient on camera were analyzed. Data were obtained from 77 patients, 42 with scalp monitoring and 35 with depth electrodes. Forty-seven percent had a left-hemisphere focus, 42% a right-hemisphere focus, and 11% multifocal seizures. The seizure focus was temporal in 68%. A magnetic resonance imaging consistent with mesial temporal sclerosis was seen in 29% of patients. Overall, 44% of the patients made at least one attempt to reach for the event bulb at the start of their seizures. Among the 72% of patients who gave a history of auras, 53% were able to press the event bulb compared to 20% with no history of auras (P = 0.016). EEG changes occurred a mean of 2.9+/-30.5 seconds after reaching for the bulb for scalp-recorded seizures (n = 20), and 16.2+/-13.7 seconds before behavior for depth-recorded seizures (n = 14, difference significant at P = 0.02). Neither seizure focus nor seizure laterality influenced the ability to press the event bulb. The authors conclude that nearly half of individuals with complex partial seizures can take volitional motor action at the start of their seizure. A method to enhance the intensity and timeliness of a seizure warning would not be wasted.

NeurologyReassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of NeurologyFisher RS, Handforth A1999; 53: 666-9

Abstract

Positron emission tomography (PET) has proven useful in epilepsy surgery for its ability to identify unilateral temporal hypometabolism (UTH), which is predictive of good surgical outcome. The significance of bilateral temporal hypometabolism (BTH) is not known.We identified all patients who had marked bilateral reduction in temporal lobe metabolism relative to the cerebellar hemispheres and compared their clinical features and treatment outcomes with those of control patients with UTH.BTH was evident in 10% of PET scans for epilepsy at our institution. We compared these patients with age-matched controls with UTH. The BTH patients had a higher percentage of generalized seizures; were more likely to have bilateral, diffuse or extratemporal seizure onsets; and had bilateral or diffuse magnetic resonance imaging (MRI) findings. UTH patients were more likely to have unilateral mesial temporal atrophy on MRI. Even when electrical seizure onsets were well localized, surgical outcomes were markedly worse in these patients than in controls. Medical treatment was also less successful. Social and cognitive functioning was worse in the BTH group. The only death occurred in the group with BTH.Patients with BTH have features distinct from those with UTH and have a worse prognosis for seizure remission after surgery.

Abstract

Evidence suggests that a specific subcortical pathway synaptically linking the anterior thalamic nuclear complex (AN) to the hypothalamus and midbrain is important in the expression of pentylenetetrazol (PTZ) seizures. Perturbation of neuronal activity along this path via focal disruption or chemical inhibition significantly raises seizure threshold. Recent data has demonstrated that focal electrical stimulation within the hypothalamic component of this pathway inhibited seizure expression in a current and frequency dependent fashion. Similar experiments were conducted in the AN to investigate the hypothesis that stimulation of this thalamic nuclear region can prevent the propagation of PTZ seizures between cortical and subcortical regions. Our results indicate that high frequency (100 Hz) stimulation of AN did not alter the expression of low dose PTZ induced cortical bursting but did raise the clonic seizure threshold compared to naive animals or those stimulated at sites near, but not in AN (P < 0.01). Low frequency stimulation (8 Hz) was in contrast, proconvulsant and could induce behavioral arrest responses accompanied by rhythmic high voltage EEG even without PTZ challenge. This data further highlights the role of AN in mediating the expression of seizures and provides experimental support for the concept that this thalamic region may be a promising target for focal stimulation to treat intractable seizures in humans.

Abstract

We evaluated the efficacy of local perfusion of diazepam (DZP) in suppression of EEG spikes and behavioral seizures produced by bicuculline methiodide (BMI) applied to rat sensory motor cortex and hippocampus.Data were obtained from 37 rats implanted with EEG head plugs and perfusion cannulas. BMI 4 mM, 5 microliters was infused on neocortex through the epidural space in 23 rats. BMI 0.1 mM, 2 microliters was infused into the left hippocampus in 14 rats.DZP 0.75-1.0 mg markedly reduced the spiking to a level of 9.9 +/- 15.8% of baseline for DZP as compared with 90.2 +/- 57.9% of baseline for vehicle-treated rats. DZP reduced spiking in a hippocampal BMI focus to 1.9 +/- 2.4% of baseline spiking, as compared with 98.0 +/- 95.6% of that in vehicle-treated animals. The amount of spread of solution was estimated with methylene blue (MB) injections. Ictal events also were attenuated. In most of the animals, systemic levels of DZP were unmeasurable and injection on the contralateral side did not reduce spiking.These findings suggest that focal application of antiepileptic drugs (AEDs) in brain may be a useful new avenue for therapy of intractable partial seizures.

Abstract

Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

Abstract

Studies examining the use of vigabatrin as monotherapy for the treatment of epilepsy are relatively scarce, and of the few that have been reported, only two were of sufficient size to provide definitive data. In both trials, vigabatrin was compared with carbamazepine for efficacy and safety. In one of these studies, carbamasepine was found to be more effective than vigabatrin in reducing seizure frequency, and the two were found to be comparably efficacious in the other study. What differed significantly, however, was vigabatrin's favorable safety profile. Vigabatrin appears to be a reasonable choice for single-drug therapy in the treatment of certain types of seizures. In other patients, it remains useful as an adjunct to other antiepileptic drugs.

Abstract

In 31 consecutive patients who were admitted to an epilepsy monitoring unit, we prospectively determined whether the patients were aware of having seizures. On admission, all patients stated that they knew of at least some of their seizures. Eight of 23 with classifiable epileptic seizures recognized that they were occasionally unaware of their seizures. During telemetry, following full recovery of consciousness after each seizure, we asked the patients whether they had recently had a seizure. For control purposes, we asked the patients the same question at random times. Among patients with seizures, there were no false-positive answers. Only 6 of 23 (26%) of the patients with epilepsy were always aware of their seizures, including complex partial and secondarily generalized events, and 7 of 23 (30%) were never aware of any seizures. Self-reporting of seizures was unreliable: Patients reporting the lowest baseline frequency of seizures had the highest fraction of unrecognized seizures. Seizure awareness was lowest for patients with temporal lobe foci, especially on the left side. Patients with primarily generalized epilepsy were more likely to be aware of tonic-clonic seizures than were patients with secondarily generalized partial seizures. All four patients with nonepileptic attacks believed that they always knew of their seizures, but only three of the four patients actually did always know. Unrecognized seizures are frequent and should be considered in patient management and in studies.

Abstract

Because titanium is widely used in neurosurgical procedures, we compared spontaneous and induced epileptiform activity in 12 rabbits with titanium clips implanted in the subarachnoid space with 12 rabbits with cobalt alloy clips and 6 rabbits that were not operated on that served as controls. Beginning 1 week after surgery, 30-minute electroencephalographic recordings were made at monthly intervals for 6 months. Recordings were scored by an electroencephalographer unaware of which treatment group was being recorded. In 48 recordings made during 6 months, no epileptiform activity was observed in any animal. Seizure threshold was evaluated by continuous intravenous injection of the convulsant drug, pentylenetetrazole (2 mg/kg/min), with continuous electroencephalographic recording. Time to spiking for the nonsurgical control group was 327 mean seconds +/- 181 standard deviation (SD), 216 mean seconds +/- 135 SD for the titanium group, and 389 mean seconds +/- 290 SD for the cobalt group. There were no significant differences among the groups (P = 0.17). Latency to behavioral tonicoclonic seizure was 1031 seconds +/- 537 SD for the group not operated on, 875 seconds +/- 334 SD for the titanium group, and 1267 seconds +/- 764 SD for the cobalt group. This study suggests that titanium clips are well tolerated within the brain and will not induce seizures.

Abstract

Electrical stimulation of the basal temporal region of the dominant hemisphere before partial temporal lobectomy for epilepsy sometimes produces temporary interruption of language function, but the significance of removal of this area is unknown. We evaluated the correlation between resection of the basal temporal language areas (BTLA) and certain types of postoperative language deficits. In a population of 25 patients, we mapped the inferolateral temporal lobe with cortical electrical stimulation, verifying the positions of the stimulating electrodes with three-dimensional computed tomography (CT). Eighty percent of the patients developed transient language deficits with stimulation, particularly with tests of confrontation naming and comprehension. BTLA was primarily located in the fusiform gyrus, from 1 to 9 cm from the temporal tip. At testing 6-12 months after operation, patients with BTLA resection performed worse (mean 9% decrease) than those with no BTLA resection (mean 4% improvement) on tests of confrontation naming (p = 0.03). Resection size accounted for less of the variance in decrease in confrontation naming than did resection of the BTLA. Tests of performance I.Q. (PIQ), verbal I.Q. (VIQ), or recognition memory for word and verbal learning showed no significant difference between these groups. Most patients do not have language decrease with removal of basal temporal lobe 5-6 cm from the tip, even with removal of BTLA. Some patients, however, have persistent decrease in naming.

Abstract

Investigators have found it difficult to separate patients with nonepileptic seizures (NES) from those with true epileptic seizures (ES) using quantitative measures of neuropsychological test performance. We examined qualitative response characteristics on the California Verbal Learning Test of 41 patients undergoing continuous video/audio-EEG monitoring in an effort to distinguish these patient groups (12 patients with left temporal [LT] foci, 11 with right temporal [RT] foci, and 18 with NES). NES patients explicitly recognized fewer target words compared with ES patients. In addition, NES patients rarely made false-positive errors, which resulted in failure to endorse a significant number of items on the recognition list. This response tendency is called a negative response bias. In contrast, LT patients endorsed a high number of items on the recognition test, which resulted in a positive response bias. RT patients demonstrated no consistent response tendency. In our sample, a negative response bias index (ie, a cutoff score < 0) showed a sensitivity of 61% and a specificity of 91%. We propose that failure to explicitly recognize words following repeated exposure may reflect aspects of psychological denial in NES patients. Response bias indices may thus help identify patients with NES and may begin to explain the psychological mechanisms underlying this complex disorder.

Abstract

Nonconvulsive status epilepticus (NCSE) accounts for approximately 20% of all status epilepticus (SE). Although convulsive SE is recognized as a medical emergency, prompt diagnosis and treatment of patients with NCSE is often not emphasized because its consequences are thought to be benign. We report 10 patients with persistent neurologic deficits or death after well-documented NCSE in the form of complex partial status epilepticus (CPSE). All patients had prolonged CPSE lasting 36 hours or longer, as documented by clinical and EEG findings. Causes for CPSE were preexisting epilepsy with partial and secondarily generalized seizures (3 patients), vascular disease (2 patients), encephalitis (2 patients), and metabolic disease (1 patient); causes were unknown for two patients. Poor outcomes identified included persistent (lasting at least 3 months) or permanent cognitive or memory loss (5 patients), cognitive or memory loss plus motor and sensory dysfunction (3 patients), and death (3 patients). NCSE in the form of CPSE is not a benign entity. Serious morbidity and mortality may occur due to the adverse effects of prolonged seizures and as a result of acute brain disorders that precipitate the seizures.

Abstract

Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.

Abstract

A diffuse electrodecremental ictal pattern (DEP) has been associated with tonic seizures and, less often, with other forms of epilepsy and has been considered to reflect a generalized seizure disorder of diffuse cortical or subcortical (brainstem) origin. In some seizures associated with DEP, however, focal ictal manifestations have been observed. We reviewed the records of all patients admitted to our seizure monitoring unit for 3 years and detected 39 patients with seizures associated with DEP. In 23 of 39 patients, clinical ictal behaviors resembled seizures of unilateral supero/mesiofrontal lobe origin and interictal EEG showed a prominent unilateral frontal component. Nine of 39 had complex absences (CA)/complex partial seizures (CPS); 4 of them were of unilateral frontal lobe origin. Seven of 39 patients had tonic or atonic seizures. Seven patients were studied further with subdural electrodes. Ictal onsets showed a high-frequency frontal lobe discharge. We conclude that in a subgroup of patients a generalized electrodecremental pattern on scalp EEG results from a regional cortical high-frequency ictal discharge originating in a single frontal lobe.

Abstract

We analyzed retrospectively the clinical and EEG data in 13 patients with simple partial seizures (SPS). All EEGs were recorded with surface electrodes with the standard 10-20 system and additional closely spaced scalp and subfrontotemporal skin electrodes. Seventy-seven seizures were recorded. We detected electrographic correlates with SPS in 10 of 13 patients (77%) and in 47 of 77 seizures (61%). The most common ictal correlates were rhythmic theta waves or spikes. Of the SPS with EEG changes, 58% were motor, 14% were sensory, and 28% were psychic seizures. Use of additional electrodes and recording channels may account for the higher incidence of EEG changes in this study than has been reported previously in the literature.

Abstract

Individuals with a history of seizures may be granted driving privileges if the risks of future seizure while driving are relatively low. Different nations have defined these risks in a wide variety of ways. Some countries, e.g., Japan, Greece, Brazil, India, and Russia, preclude driving after a single seizure. Other countries, such as Canada and the United States, allow driving < or = 3 months after certain types of seizures. A Joint Commission of the International Bureau for Epilepsy/International League Against Epilepsy has summarized regulations in several countries. From a consideration of medical literature and existing practices, a series of proposed guidelines for driving and epilepsy is recommended. In general, these guidelines suggest use of a seizure-free interval, generally 1-2 years but less in particular instances, to determine fitness to drive. Required physician reporting is discouraged, but physicians should report patients whom they believe pose a danger to themselves and to public safety. Individualized consideration should be given to special circumstances that may modify a general driving prohibition. Education and information programs are necessary for medical and regulatory authorities to develop a rational approach to driving and epilepsy worldwide.

Abstract

Recent advances in clinical epilepsy have included improved systems for classifying seizures and epileptic syndromes, better definition of nontemporal seizures, improved methods for distinguishing syncope and pseudoseizures from epilepsy, and new approaches in the management of pregnant women with epilepsy. There has been continued development of the concept that epilepsy is a heterogeneous disorder with many imitators. Treatment is most successful when tailored to the particular seizure type, epileptic syndrome, and special needs of the individual patient.

Abstract

We conducted a study to explore how electroencephalographers (EEGers) read EEGs and reach clinical impressions based upon them. Eight EEGers and a rule-based computerized "spike" detector marked epileptiform discharges ("EDs") in 12 test records. Of all marked events, 18% were marked by all readers and 38% were marked by only one reader. Readers agreed on basic clinical features of the records, such as whether a record demonstrated EDs, the rank order of ED sources by location, and the ranking of test records in order of the number of EDs detected. Readers marked records in a consistent pattern that was independent of an objective measure of expertise and experience. Our computerized ED detector had lower sensitivity and selectivity than human readers, but either parameter could be adjusted to be comparable to human EEGers at the expense of the other. We propose that EEGers employ reproducible, quantitatively different styles of reading EEG tracings to reach qualitatively similar clinical impressions. In practice, EDs are not absolutely defined, but appear to represent a continuum of activity which lends itself better to description and rank ordering than to absolute quantitation. More than just counting EDs, a successful computerized ED detector should be adaptable to the style of individual readers in order to help them efficiently formulate their clinical impressions.

Abstract

The introduction of several new antiepileptic drugs in the United States is likely in 1993. Many new drugs have undergone testing, but the four currently considered the most important are felbamate, gabapentin, lamotrigine, and vigabatrin. When these drugs are used as add-on therapy for patients with intractable epilepsy, 20 to 60% of patients show at least a 50% improvement in seizure frequency and 7% become seizure free. An overview of these agents is presented.

Abstract

Little is known about what pathways subserve mirth and its expression laughter. We present three patients with gelastic seizures and laughter elicited by electrical stimulation of the cortex who provide some insight into the mechanisms of laughter and its emotional concomitants. The first patient had seizures manifested by laughter without a subjective feeling of mirth. Magnetic resonance imaging showed a cavernous haemangioma in the left superior mesial frontal region. Ictal subdural electrode recording showed the seizure onset to be in the left anterior cingulate gyrus. Removal of the lesion and of the seizure focus rendered the patient virtually seizure free over 16 months of follow-up. The other two patients had complex partial seizures of temporal lobe origin. Electrical stimulation of the fusiform gyrus and parahippocampal gyrus produced bursts of laughter accompanied by a feeling of mirth. These cases reveal a high likelihood of cingulate and basal temporal cortex contribution to laughter and mirth in humans, and suggest the possibility that the anterior cingulate region is involved in the motor act of laughter, while the basal temporal cortex is involved in processing of laughter's emotional content in man.

Abstract

Sphenoidal electrodes are used to localize epileptiform activity originating in the temporal lobe during complex partial seizures. Sphenoidal electrodes, however, are semi-invasive and uncomfortable to the patient. We compared skin electrodes placed on the cheek ("cheek electrodes") with sphenoidal electrodes for the detection of the side and site of complex partial seizure onset. In a masked, randomized comparison of single ictal recordings in 22 patients, there were no significant differences between sphenoidal and cheek electrode montages in detecting the side or site of ictal onset (P < 0.01). Signal/noise ratios for interictal spikes were a mean 16.5% greater at sphenoidal sites compared to cheek sites (paired t test, t = 2.4, P < 0.05). This difference, however, did not influence the detection of rhythmical ictal activity in cheek and sphenoidal montages in our study, nor the assignment of side, site or time of seizure onset by unbiased readers. Recordings from cheek electrodes are comparable to those from sphenoidal electrodes and are useful for localizing ictal activity.

Abstract

Stimulation of centromedian (CM) thalamic nuclei has been proposed as a treatment for seizures. We implanted programmable subcutaneous (s.c.) stimulators into CM bilaterally in 7 patients with intractable epilepsy to test feasibility and safety. Stimulation was on or off in 3-month blocks, with a 3-month washout period in a double-blind, cross-over protocol. Stimuli were delivered as 90-microseconds pulses at 65 pulses/s, 1 min of each 5 min for 2 h/day, with voltage set to half the sensory threshold. Stimulation was safe and well-tolerated, with a mean reduction of tonic-clonic seizure frequency of 30% with respect to baseline when stimulator was on versus a decrease of 8% when the stimulator was off. There was no improvement in total number of generalized seizures with stimulation, and treatment differences were not statistically significant. Stimulation at low intensity did not alter the EEG acutely, but high-intensity stimulation induced slow waves or 2-3 Hz spike-waves with ipsilateral frontal maximum. In an open-label follow-up segment with stimulator trains continuing for 24 h/day, 3 of 6 patients reported at least a 50% decrease in seizure frequency. There were no side effects. This pilot project demonstrated the feasibility of controlled study of thalamic stimulation in epilepsy, but further study will be needed to demonstrate efficacy.

Abstract

Frequencies above 35-40 Hz are poorly visualized on conventional EEG scalp recordings. We investigated frequency components up to 150 Hz in digitally recorded EEGs of seizures in five patients with implanted subdural grids, as part of their evaluation for epilepsy surgery. Amplifier bandpass was set from 0.1 to 300 Hz, and EEG was digitized at 2,000 samples per second. Seizures with electrodecremental patterns at the start showed a significant increase in spectral power above 35 Hz, with a twofold increase in the 40-50-Hz range, and up to a fivefold increase in the 80-120-Hz portion of the spectrum. Activity above 40 Hz could represent summed action potentials, harmonics of synaptic potentials or transient sharp components of synaptic potentials. High-frequency increases were largely localized to the region of the seizure focus. Grid sites remote from the focus did not show significant energy in the EEG band above 40 Hz at baseline, nor at time of seizure onset. Our findings suggest that high-frequency recordings may be of use in localizing seizure foci.

Abstract

Classic neurosurgical teaching holds that once the Rolandic fissure (Rf) has been located, there are distinct differentiated primary motor and sensory functional units confined within a narrow cortical strip: Brodmann's Areas 4 and 6 for primary motor units in front of the Rf and 3, 1, and 2 for sensory units behind the Rf. To test this assumption, we examined in detail the records of cortical mapping done by electrical stimulation of the cerebral cortex via implanted subdural electrode grids in 35 patients with seizure disorders. Of 1381 stimulations of the electrode sites, 346 (25.1%) produced primary motor or motor-arrest and sensory responses in contralateral body parts: 56.8% were primary motor responses; 16.2% were motor-arrest; 22.5% were sensory; and the remaining 4.5% were mixed motor and sensory responses. Two-thirds (65.9%) of the primary motor responses were located within 10 mm of the Rf, and the remaining one-third (34.1%) were more than 10 mm anterior to the Rf or were posterior to the Rf. Furthermore, in the patient group with brain lesions, fewer than one-third (28.1%) of the responses were within the 10-mm narrow anterior strip. Our study reconfirmed that a significant number--at least one-third--of motor responses are distributed outside the classic narrow cortical strip. In patients with brain lesions, the motor representation is further displaced outside the narrow strip. This finding indicates that primary motor cortex may extend beyond the gyrus immediately anterior to the Rf.

Abstract

Evaluation of outcome of epilepsy surgery is complex because of several factors. Epilepsy is itself a heterogeneous disorder. Different epilepsy centers encounter different referral mixes of patients. Institutions employ various methods for pre-operative evaluation and widely varying surgical techniques. Clear definitions of surgical success and reliable scales for its measurement are lacking. Few data are acquired prospectively and maintained in a format allowing inter-institutional collation of results. A better representation of surgical outcome could in the future be served by adherence to 4 principles: collection of common data in standard formats; comparison of like, rather than disparate, populations; maintenance of quantitative data in raw form; and measurement of outcome along several dimensions or scales. Psychosocial issues have been underemphasized in most prior analyses of outcome.

Abstract

Alterations in a variety of neurotransmitter systems have been identified in experimental models of epilepsy and in brain tissue from patients with intractable temporal lobe seizures. The availability of new high-affinity radioligands permits the study of some neuroreceptors in vivo with positron emission tomography (PET). We previously characterized the in vivo binding of 11C-carfentanil, a potent and selective mu opiate receptor agonist, and described increases in 11C-carfentanil binding in the temporal neocortex of patients with unilateral temporal lobe epilepsy. These studies have been extended to 11C-diprenorphine, which labels mu, kappa, and delta opiate receptor subtypes. Paired measurements of opiate receptor binding were performed with PET using 11C-carfentanil and 11C-diprenorphine in patients with unilateral temporal lobe seizures. Carfentanil binding, reflecting changes in mu opiate receptors, was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. Diprenorphine binding, reflecting mu as well as non-mu opiate subtypes, was not significantly different among regions in the focus and nonfocus temporal lobes. Regional glucose metabolism, measured using 18F-2-fluoro-2-deoxyglucose, was decreased in the mesial and lateral aspects of the temporal lobe ipsilateral to the epileptogenic focus. The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of opiate subtypes in unilateral temporal lobe epilepsy.

Abstract

As surgical treatments for adult and pediatric forms of epilepsy have become more refined, methods for noninvasive localization of epileptogenic foci have become increasingly important. Detection of focal brain metabolic or flow abnormalities is now well recognized as an essential step in the presurgical evaluation of many patients with epilepsy. Positron emission tomography (PET) scanning is most beneficial when used in the context of the total clinical evaluation of patients, including scalp EEG, invasive EEG, neuropsychologic testing, etc. Metabolic PET studies also give insight into pathophysiologic mechanisms of epilepsy. The dynamic nature of the interictal hypometabolism observed with 18[F]FDG in some patients suggests that excitatory or inhibitory neurotransmitters and their receptors may be involved. An exciting current application of PET scanning is the use of tracers for neurotransmitter receptors in the study of epilepsy patients. Mu and non-mu opiate receptors have been extensively studied and are beginning to give new insights into this disorder. Increased labeling of mu receptors in temporal neocortex using 11C-carfentanil has been demonstrated and, in some patients, supplements the clinical localization information from 18[F]FDG studies. Increased mu opiate receptor number or affinity is thought to play a role in anticonvulsant mechanisms. Specificity of increased mu receptors is supported by the absence of significant changes in non-mu opiate receptors. Other brain receptors are also of interest for future studies, particularly those for excitatory neurotransmitters. Combined studies of flow, metabolism, and neuroreceptors may elucidate the factors responsible for initiation and termination of seizures, thus improving patient treatment.

Abstract

The intracarotid amobarbital sodium, or Wada, test has been used to localize speech and memory function prior to surgical treatment of temporal lobe seizures. The authors mixed technetium-99m hexamethyl-propyleneamine oxime (HMPAO) with amobarbital sodium and injected the mixture in 25 patients with epilepsy. Single photon emission computed tomography (SPECT) of the brain was then performed to determine intracerebral distribution of the amobarbital sodium. Results of SPECT were compared with those of conventional and digital subtraction angiography (DSA). The distribution of Tc-99m HMPAO and, presumably, amobarbital sodium varied from patient to patient. SPECT revealed a statistically different distribution from that predicted with conventional angiography. The distribution also often differed from that of DSA, although the difference was not significant. SPECT revealed infrequent delivery to mesial temporal lobe structures. This emphasizes the need for caution in the use of the intracarotid amobarbital sodium test to predict the outcome of removal of these areas.

Abstract

Driving and epilepsy is a problem that involves physicians as both care providers to patients and consultants to regulatory authorities. Driving restrictions for people with seizure disorders are intended to ensure the public's safety, but such restrictions may unduly harm the welfare of many people with seizures. In the United States, all states now permit some people with epilepsy to drive. In general, only people whose seizures are adequately controlled are licensed to drive. Adequate control has been judged principally by the seizure-free interval, but individual state standards widely vary. There is a trend toward greater liberalization of driving standards for people with seizure disorders, but the appropriateness and application of these standards continue to raise questions, as does the role physicians should have in the licensing process. Our responsibilities to persons with disabilities and advances in our understanding of seizures and the nature of driving risks warrant a reappraisal of the current medical, legal, and social implications of driving and epilepsy.

Abstract

Measurement of serum prolactin levels can be useful in the diagnosis of epilepsy, since prolactin levels often rise after seizures, but not after most imitators of epilepsy. Utility of the test is limited by the need to obtain blood 10 to 20 minutes after the episode. The present study documents the validity of prolactin measurements using capillary blood, which was obtained by the finger-stick method after a possible seizure and then applied to filter paper. Venous and capillary prolactin levels were determined 10 to 20 minutes after seizure-like episodes in 20 patients who were studied in an epilepsy monitoring unit. Venous and capillary prolactin values correlated, with a Pearson coefficient of 0.90. Using a criteria of any elevation above the laboratory upper limit of normal, capillary prolactin values correctly identified seizure versus pseudoseizure in 9 (100%) of 9 patients with generalized tonic-clonic seizures, in 5 (71%) of 7 patients with complex partial seizures, and 4 (100%) of 4 patients with pseudoseizures. Prolactin values were unaffected by leaving filter paper samples at room temperature for up to 1 week. This study suggests the utility of diagnostic capillary blood collection kits to assist in the diagnosis of epilepsy in outpatients.

Abstract

Abolition of speech production after intracarotid amobarbital injection is generally considered evidence for language laterality. However, complex auditory comprehension may be preserved after injection of the dominant (left) side. The possibility that this sparing may be due to the intracarotid amobarbital injection not adequately deactivating some of the areas responsible for speech comprehension in the posterior part of the hemisphere was tested with a task known to be critically dependent on the left posterotemporal-inferoparietal region, one assessing visuo-verbal semantic relatedness. Even when the intracarotid injection of the left side produced marked deficits of speech production, comprehension of semantic relations was still intact in eight of 15 patients. Ten of these 15 patients also received right carotid injections, none of which affected comprehension of semantic relatedness. These data indicate that the intracarotid amobarbital injection cannot always specify the laterality of all language functions, an important concern when considering surgical procedures in the dominant posterotemporal-inferoparietal region.

Abstract

It would appear from the above that Pritchard agrees with the use of some agents other than magnesium sulfate that have known anticonvulsant properties. We believe that the subject at issue is whether magnesium sulfate should be used in treating the seizures of eclampsia. In our "Controversies" article, we do not address the issue of whether magnesium sulfate modifies pathophysiological factors leading to preeclampsia, but restrict ourselves to the treatment of the seizure per se, once seizures supervene, and the avoidance of their recurrence. The pathophysiological mechanisms and optimal treatment of preeclampsia and of eclampsia (excepting seizures) remain to be determined, as does the use of magnesium sulfate in this condition. Eclamptic seizures are clinically and electroencephalographically indistinguishable from generalized tonic-clonic seizures. Whether seizures arise in or out of the setting of preeclampsia, they should be treated as are other seizures, with known anticonvulsants. Controlled clinical trials are needed to address the effectiveness of alternative antiseizure regimens.

Abstract

Effects of dextrorphan (DX), a metabolite of the over-the-counter antitussive, dextromethorphan, were investigated in rat hippocampal slices exposed to the epileptogenic agent penicillin. At 50 microM and 100 microM concentrations dextrorphan suppressed late components of the epileptiform CA1 field potential elicited by afferent electrical stimulation, and partially suppressed the intracellularly recorded paroxysmal depolarization shift. These effects were not due to non-specific changes in cell excitability, since resting cell membrane potential, input resistance, and the ability of cells to fire action potentials in response to direct depolarizing current were unaffected. The depressant effect of 100 microM dextrorphan was probably due to actions at the NMDA receptor, since pretreatment with the competitive NMDA antagonist D-APV prevented any further depressant effects of dextrorphan in this model. In contrast, at a 10 microM concentration DX enhanced the amplitude of evoked epileptiform field potentials and intracellularly recorded EPSPs. These findings support a role for dextrorphan and similar agents as anticonvulsants at high concentrations, but raise a caution regarding possible excitatory actions of dextrorphan at low concentrations.

Abstract

We evaluated 5 consecutive patients with subdural grid electrodes (including placement over the left basal temporal region) for focal resections for control of intractable epilepsy. All 5 had language dysfunction when we performed cortical stimulation over the basal temporal region (the inferior temporal gyrus, the parahippocampal gyrus) using a systematic battery of language tests. The area in which language interference could be produced began from at least 11 to 35 mm posterior to the temporal tip and ended at least 39 to 74 mm posterior to the temporal tip. The most consistently impaired language tasks were spontaneous speech and passage reading, but there was impairment of all language functions tested in some patients. Language deficits after dominant temporal lobectomy may result from resection of this area.

Abstract

Safe parameters for electrical cortical stimulation in humans are difficult to estimate from the animal experimental literature. We therefore examined the light microscopic histology at a total of 11 sites of direct subdural electrical stimulation, taken as part of anterior temporal lobectomies in 3 patients. Stimulations had been done through 3.175 mm diameter electrodes, with 0.3 msec square wave pulses of alternating polarity at 50 pulses/sec. In 2 patients, one site each had been used as a common reference for stimulation, receiving over 251 stimulation trials, most of 2-5 sec duration, at currents of 12.5-15.0 mA, 1 day prior to resection. The maximum charge per phase was 4.0-4.4 microC; the maximum charge density was 52-57 microC per geometric cm2 per pulse at the electrode surfaces. Comparison of hematoxylin and eosin, periodic acid-Schiff, and cresyl violet-stained material from the electrode sites with that from other regions did not show any histologic abnormalities attributable to the electrical stimulation. The relatively brief and intermittent periods utilized for human stimulation testing do not appear to cause structural damage at the light microscopic level at charge densities that exceed the threshold for damage established in animal studies with more continuous, chronic stimulation schedules.

Abstract

We performed a double-blind, crossover, add-on study of the antitussive agent dextromethorphan (DM 120 mg/d) as therapy for seizures on 9 patients suffering from severe complex partial seizures. DM had no significant influence on key laboratory values, nor on anticonvulsant drug levels. Side effects were negligible. Complex partial seizure frequency increased 25% during the DM arm of the study, although this increase was not clinically significant.

RESECTION OF THE EPILEPTOGENIC AREA IN CRITICAL CORTEX WITH THE AID OF A SUBDURAL ELECTRODE GRID10TH MEETING OF THE WORLD SOC FOR STEREOTACTIC AND FUNCTIONAL NEUROSURGERYUematsu, S., Lesser, R., Fisher, R., Krauss, G., Hart, J., Vining, E. P., Freeman, J., GORDON, B.KARGER.1990: 34–45

Abstract

Electrode grids were implanted subdurally in 28 patients with epilepsy. In 16 of the 28 patients, an epileptogenic area was located in the speech-dominant left temporal lobe. Recordings made with the grid revealed that the epileptogenic areas in the patients varied widely in extent: the area was confined within the first 10 mm of the temporal lobe in some patients or it was scattered throughout the entire anterior to posterior 80-mm extend in others. Resection of the epileptogenic area was adjusted accordingly in each case. In 6 of 16 patients who were left-hemisphere-dominant for language, up to 55-80 mm from the tip of the temporal lobe was removed, a measure that exceeds the conventional limit of 50 mm from the tip of the dominant hemisphere. In the remaining 12 of the 28 patients, epileptogenic areas were located in a combination of several lobes. In 7 of these 12 patients, the epileptogenic area encompassed the rolandic area; it was removed without deficit in 4 patients and with expected deficit in 3. Of the latter 3 patients, 1 patient underwent hemispherectomy, and a large portion of the epileptogenic rolandic cortex in the frontal and parietal lobes was removed from the other 2. There were 2 cases of grid-related infection, which cleared with antibiotic treatment; there were no lasting complications of grid implantation in any patient. There was no mortality. Electroencephalographic recording and functional mapping using subdural electrode grids allow a tailored, maximal resection of epileptogenic tissue with minimal injury to critical cortex.

Abstract

We have developed a model of cyclosporin A (CsA) central nervous system toxicity in the Munich-Wistar rat in which CsA, 20 mg/kg/day i.p., produces significant EEG abnormalities and mortality. In the present study we used cohorts of Munich-Wistar rats to assess effects of CsA on the threshold for tonic-clonic electroshock-induced seizures. Rat cohorts were begun on cremephore, CsA-10 mg/kg/day, or CsA-20 mg/kg/day. On day 7 and day 14 of the dosing protocol, cohorts of animals were exposed to maximal electroshock (MES) using a minimal staircase method within each cohort. Multiple logistic regression models were used to determine differences between groups on the relative odds of producing a MES-induced seizure while controlling for other variables. Seizure threshold was significantly affected by shock amperage and body weight, but not by SUN, creatinine, bilirubin, sodium, potassium, weight loss or day the shock was delivered. The odds ratios of seizure induction in the CsA-treated groups versus placebo group were 1.91 for CsA-10 mg/kg/day and 3.63 for CsA 20-mg/kg/d, both statistically significant. These results suggest that cyclosporine lowers seizure threshold and probably increases susceptibility to seizures, the etiology of which may be multifactorial clinically.

Abstract

Conceptual advantages, together with advances in both technique and technology, have considerably altered the approach to intractable epilepsy over the past two decades. Appropriate utilization of these advances allows our evaluation of patients with intractable seizures to be much more precise and specific than was once the case and allows us to improve considerably our ability to treat patients with intractable epilepsy. We propose an algorithm for the evaluation and treatment of patients with intractable complex partial seizures. Other forms of intractable epilepsy may benefit from similar diagnostic and therapeutic approaches.

Abstract

Magnesium sulfate has been used as an anticonvulsant in the treatment of eclampsia, but efficacy of magnesium in other types of seizure disorders is poorly documented. We examined the effects of magnesium sulfate (MgSO4) on seizures produced in mice by maximal electroshock (MES) and pentylenetetrazol (PTZ), MgSO4 injection (6.7 mEq/kg i.p.) caused weakness in all animals. With suprathreshold electroshock, 10/10 controls and 11/12 treated animals had seizures with tonic hind limb extension (P = NS). Electroshock threshold was unaltered by magnesium treatment (n = 48; P = 0.47). PTZ induced clonic seizures in 12/12 controls and 5/14 treated animals (P less than 0.05). This difference was likely due to muscular weakness because frequency of EEG spikes was the same in PTZ and PTZ + MgSO4 groups. Mean serum magnesium levels were 2.3 +/- 0.3 mEq/l in animals not given MgSO4; 10.9 +/- 1.4 mEq/l and 12.8 +/- 2.2 mEq/l in treated animals with and without seizures (P = NS). We conclude that magnesium sulfate had no significant anticonvulsant activity in mouse MES and PTZ models for epilepsy. The relevance of these findings to the possible efficacy of magnesium sulfate in eclamptic seizures and other types of epilepsy remains to be determined.

Abstract

The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p. Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEG's recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEG's; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEG's and/or seizures seen in 58 +/- 15% of these rats (P = 0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEG's. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEG's. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.

Abstract

The study of mechanisms of the epilepsies requires employment of animal models. Choice of a model system depends upon several factors, including the question to be studied, the type of epilepsy to be modelled, familiarity and convenience. Over 50 models are reviewed. Major categories of models are those for simple partial seizures: topical convulsants, acute electrical stimulation, cortically implanted metals, cryogenic injury; for complex partial seizures: kainic acid, tetanus toxin, injections into area tempesta, kindling, rodent hippocampal slice, isolated cell preparations, human neurosurgical tissue; for generalized tonic-clonic seizures: genetically seizure-prone strains of mouse, rat, gerbil, fruitfly and baboon, maximal electroshock seizures, systemic chemical convulsants, metabolic derangements; and for generalized absence seizures: thalamic stimulation, bilateral cortical foci, systemic penicillin, gamma-hydroxy-butyrate, intraventricular opiates, genetic rat models. The lithium-pilocarpine, homocysteine and rapid repetitive stimulation models are most useful in studies of status epilepticus. Key findings learned from each of the models, the model's strengths and weaknesses are detailed. Interpretation of findings from each of these models can be difficult. Do results pertain to the epilepsies or to the particular model under study? How important are species differences? Which clinical seizure type is really being modelled? In a model are behavior or EEG findings only similar superficially to epilepsy, or are the mechanisms comparable? The wealth of preparations available to model the epilepsies underscores the need for unifying themes, and for better understanding of basic mechanisms of the epilepsies.

Abstract

The effects of dextrorphan (DX) and dextromethorphan (DM) on responses to excitatory amino acids in the CA1 region of the hippocampus of the rat were studied using extracellular and intracellular recording in in vitro slices of brain. Dextrorphan selectively and non-competitively blocked depolarizations evoked by focally-applied N-methyl-D,L-aspartate (NMA), recorded by both extracellular and intracellular techniques. Quisqualate (QUIS) responses and evoked field potentials were not affected by DX. Epileptiform activity elicited in Mg2+-free solution was suppressed by DX. Dextrorphan had no effect on resting membrane potential or input resistance. The antagonism of NMA by DX was dose-dependent with an EC50 of 0.65 microM; DM was also effective but considerably less potent. In the paradigm used in the present study, DX did not produce the clear use-dependent block observed in the presence of MK-801. These data suggest that DX, the metabolite of the widely used antitussive DM, is a potent NMDA antagonist with a potential role as an anticonvulsant and neuroprotective agent.

Abstract

The effect of prolonged glutamate (GLU) application was examined on 60 CA1 pyramidal neurons in the in vitro rat hippocampal slice preparation. Continuous application of L-GLU, either by bath perfusion (0.5-2 mM) of the slices or iontophoresis (200 mM) into the dendritic region of the neurons, elicited a transient depolarization which faded to a mean of 53% of the initial peak amplitude despite continued exposure to the agonist. Membrane depolarization to aspartate (ASP) and the d-isomer of GLU also faded with time. In contrast, the depolarizing response to the excitatory amino acid agonists N-methyl-D,L-aspartate (NMA), quisqualate (QUIS), and kainate (KA) did not fade significantly during continuous application. The fade of the GLU depolarization was not affected by the NMDA antagonist D-2-amino-5-phosphonovalerate (APV) or by blocking synaptic transmission with tetrodotoxin. At the time of maximum fade of the GLU depolarization, there was no change in input resistance or GLU reversal potential. In addition, fade of the response was not a consequence of changes in extracellular potassium concentration, GLU uptake mechanisms, or the electrogenic pump. The most likely explanation for fade is postsynaptic receptor desensitization.

Abstract

An unsuccessful attempt to terminate myoclonic status epilepticus with elevation of serum magnesium levels is described. During 3 days, serum magnesium was increased from 1.5 mEq/L to 14.2 mEq/L by continuous i.v. infusion of 3-6 g/h of magnesium sulfate. Other anticonvulsants were maintained at nearly constant levels. Cerebrospinal fluid magnesium was 3.5 mEq/L during the infusion. Despite magnesium-related neuromuscular blockade and accompanying cessation of visible myoclonus, the electroencephalogram revealed ongoing blunted sharp-wave activity at the baseline frequency. Transient complications of the infusion included prolongation of the PR interval on the electrocardiogram, hypomotility of the gastrointestinal tract, and peripheral muscle flaccidity, all of which resolved within 24 h of return to normal serum magnesium levels. These results suggest that the therapeutic role of magnesium in myoclonic status epilepticus is limited.

Abstract

The time course of recovery in the Guillain-Barré syndrome is known to vary widely, but factors associated with differences have not been previously defined. In this study we used multivariate analysis to identify such factors and to determine whether the presence or absence of specific factors would influence treatment decisions, particularly the use of plasmapheresis. Data from 245 patients randomized into conventional and plasmapheresis arms were used to assess the time to walk independently (Grade 2), the time to improve one grade, and the percentage improved at 4 weeks. Individually, many factors were associated with outcome. In the multivariate analysis, four factors correlate with poorer outcomes: mean amplitude of compound muscle action potential on stimulating distally of 20% of normal or less, older age, time from onset of disease of 7 days or less, and need for ventilatory support. The most powerful predictor of outcome was the abnormal mean amplitude of compound muscle action potential on stimulating distally. Plasmapheresis, the only variable the physician can influence, has a beneficial effect over and above any or all of these factors. The plasmapheresis patients on continuous flow machines had better outcomes than those on intermittent flow machines. From these data, tables of expected outcome probabilities have been developed.

Abstract

Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.

Abstract

Carbamazepine is a drug of choice for partial epilepsies, certain affective disorders and neuralgic pain syndromes. It has an excellent safety record; however, overdose can be dangerous. This article reports one of the very few fatalities from carbamazepine overdosage, in an individual with a peak carbamazepine level of 54 mg/L. Manifestations of this and other major carbamazepine overdoses reviewed from the literature were similar to those of tricyclic - anticholinergic overdose, with coma, hypotension, respiratory depression, cardiac arrhythmias, abnormal movements and seizures. Fatality from cardiovascular causes occurred despite decline of serum carbamazepine levels to the putatively non-toxic range, emphasizing the potential for delayed consequences of carbamazepine overdosage. Management should consist of vigorous gastric lavage and installation of activated charcoal, full supportive care in a monitored setting and consideration of early charcoal hemoperfusion, before the patient becomes hypotensive.

Abstract

A technique of locating current dipoles in spherical conducting volumes by determining the location of the magnetic field maximum and inverting the magnetic field equations was developed and the expected localisation errors were predicted. AC current dipoles were placed in spheres of uniform conductivity. Each dipole's magnetic field was measured and its location was calculated by determining the angle between the magnetic field null and maximum and using an iterative inverse solution to the magnetic field equations. Absolute agreement between predicted magnetic field strengths and actual magnetic field measurements was within 5%. A study of the effect of signal to noise ratio and number of data points in the analysis indicates that dipole localisation of approximately 1 mm is achievable for a signal to noise ratio greater than 10 decibels (S/N greater than 10 db).

Abstract

N-methyl-D,L-aspartate (NMA) antagonists are of potential value in the treatment of epilepsy and ischemia, but commonly utilized compounds are of low potency and poorly penetrate the brain. Tiletamine hydrochloride is a lipophilic and potent veterinary anesthetic. This study shows tiletamine to be similar to ketamine and to phencyclidine, agents known to interact with the NMA receptor. Effects of tiletamine on synaptic transmission and on direct excitatory responses to exogenous amino acids were examined in rat hippocampal and striatal slices. In striatal slices, tiletamine inhibited the NMA-mediated, but not the spontaneous, release of [3H]acetylcholine, with an IC50 of 70 nM. In hippocampal CA1 cells, 3 microM tiletamine in the perfusate reversibly blocked the intracellularly recorded responses to ionophoretically applied NMA, but not to glutamate, quisqualate and kainate. Tiletamine, 3 to 100 microM, had no effect on the orthodromically elicited excitatory postsynaptic potential, action potential amplitude or duration, resting membrane potential, or input resistance. In Mg++-free perfusate, the excitatory postsynaptic potential was greatly augmented to give a paroxysmal depolarization shift and was reversibly blocked by 10 microM tiletamine. Our results show that tiletamine is a potent and reversible antagonist of NMA-mediated responses without itself having major effects in low concentrations on normal membrane and synaptic pyramidal cell properties.

Abstract

Depth EEG recordings were carried out in 16 patients with clinical and EEG evidence of the Lennox-Gastaut syndrome (LGS), in attempts to identify a surgically-resectable focus. Structures explored included the mesial temporal (amygdaloid) areas, the orbito-frontal cortex, the superior parasagittal cortex, and in three cases deep cerebellar nuclei. All patients showed disordered and slow background activity in depth leads. Slow spike-waves were prominent in orbito-frontal and parasagittal frontal areas, but were generally reflected as well in surface frontal leads. Runs of rapid spikes were recorded in 7 patients, again mainly in deep frontal leads. Independent interictal spikes were observed in 9 patients, chiefly from one or both amygdaloid areas. Ictal events were recorded in 9 patients. Frontal lobes were most often involved at the start, and a few cases showed origin of apparently generalized surface activity beginning unilaterally in deep frontal lobe. None of the identified interictal nor ictal foci were sufficiently dominant to justify local surgical resection. Frontal bilateral synchrony, when present, was adequately visualized by noninvasive surface EEG recording. Depth electroencephalography in our hands therefore has a very limited role in evaluation of patients with LGS.

Abstract

Effects of prolonged (5-10 min) continuous perfusion of excitatory amino acids on penicillin (PEN)-evoked epileptiform activity in hippocampal slices were examined with extracellular and intracellular recordings. L-glutamate (GLU), L-aspartate (ASP), quisqualate (QUIS), and N-methyl-D,L-aspartate reversibly depressed multiple (epileptiform) population spikes elicited by PEN (1.7 mM). Intracellularly recorded, PEN-evoked paroxysmal depolarization shifts (PDS) were partially blocked by 1 mM GLU and largely eliminated by 2 mM GLU or ASP. In the presence of PEN, perfusion with both GLU and ASP induced a transient 4 to 6-mV depolarization, usually followed by spontaneous return of membrane potential to control levels. During the amino acid (AA)-induced block of epileptiform activity, there was no significant change in resting membrane potential, input resistance, or the ability to fire action potentials in response to depolarization, indicating that the decreased responsiveness is not a consequence of nonspecific pyramidal cell overdepolarization. The observed depression of epileptiform activity by continued exposure to GLU and its analogues may reflect desensitization or another regulatory mechanism to limit overexcitation.

Abstract

Exposure of rat hippocampal slices to perfusate containing 1-2 mM glutamate (GLU) induces reversible and relatively selective blockade of excitatory transmission. Intracellular recordings from 20 region CA1 hippocampal cells demonstrated only transient and mild effects on resting membrane properties and action potentials. In contrast, in 2 mM GLU excitatory postsynaptic potentials declined to 28% of control (P less than 0.001); inhibitory postsynaptic potentials remained robust at 88% of control. This suggests that excess exposure to GLU may result in a selective 'down-regulation' of excitatory synaptic transmission, while preserving inhibitory pathways. These observations may have practical implications for development of new anticonvulsant drugs.

Abstract

There has been considerable progress in various segments of epileptology over the past two to three decades. The diagnostic sector has benefited from more advanced and sophisticated EEG-related techniques. The advent of computerized tomography has expedited the clinical evaluation of epileptic patients and new high-technology methods have been introduced. A new type of diagnostic subdivision (based on age-determined epileptic conditions and certain epileptic syndromes) is of great practical significance because of its prognostic implications (distinction of basically benign and severe forms of epileptic seizure disorders). The therapeutic sector has been stimulated by the introduction of new antiepileptic medications and particularly by profound insights into metabolic and pharmacokinetic characteristics of anticonvulsants; this has resulted in the introduction of techniques for serum level determinations. There have been new developments in the field of neurosurgical treatment of epileptic seizure disorders.

Abstract

The dipeptide N-acetylaspartylglutamate (NAAG), and possibly the related dipeptide aspartylglutamate (AG), have been found in high concentrations in rat brain, and have been shown to bind avidly and selectively to a subset of glutamate (GLUT) receptors. Certain observations regarding GLUT and aspartate might be explained if the endogenous transmitter were a compound composed of both amino acids. We therefore examined the electrophysiological actions of NAAG and AG in the rat in vitro rat hippocampal slice model. NAAG or AG and GLUT were applied locally to cells by a dual-barrel pressure technique. Intracellular recordings from 34 CA1 pyramidal neurons showed depolarizations and conductance increases resembling evoked excitatory postsynaptic potential in 15 of 20 cells exposed to NAAG, and 14 of 14 exposed to AG. Many GLUT-responsive sites did not respond to AG, and most did not respond to NAAG. Responses to NAAG were usually too small to induce cell firing; they were best detected, therefore, by intracellular recording. With extracellular unit recordings, GLUT was equally excitatory in stratum radiatum and pyramidale of CA1 (N = 19; p greater than 0.10, one-way analysis of variance). In contrast, AG was considerably more potent (N = 21; p less than 0.01) in stratum radiatum. NAAG was not noted to excite cells when applied to stratum pyramidale. The region of maximal responsiveness to AG in CA1 coincided with the area of the dendritic tree receiving Schaffer collateral-commissural afferents. This spatial profile, together with other neuropharmacological evidence, support the candidacy of glutamate-containing peptides as endogenous excitatory compounds in certain pathways of hippocampus.

Abstract

Depression of GABA-mediated IPSPs has been proposed to be a crucial factor in the onset of epileptiform activity in most models of epilepsy. To test this idea, we studied epileptiform activity induced by bath application of the excitatory neurotoxin kainic acid (KA) in the rat hippocampal slice. Repetitive field potential firing, spontaneous or evoked, occurred during exposure to KA. Intracellular records from 52 CA1 pyramidal cells during changes from control saline to saline containing 1 microM KA indicated that KA depolarized cells an average of about 5 mV and caused a 15% decrease in input resistance. Action potentials and current-induced burst afterhyperpolarizations did not change significantly. In several cells the tonic effects of KA were preceded by a transient phase of sporadic, spontaneous depolarizations of 2 to 10 mV and 50 to 200 msec duration. These phasic depolarizations were blocked by hyperpolarization. The major effect of 1 microM KA was a depression of synaptic potentials. Initially, KA depressed fast GABA-mediated IPSPs and slow, non-GABA-mediated late hyperpolarizing potentials to 23% and 40% of control values, respectively. IPSP depression correlated closely with onset of burst potential firing in response to synaptic stimulation. Similar observations were made on six cells from the CA2/3 region, although these cells were affected by lower doses of KA. The mechanism of IPSP depression was studied by using KCl-filled electrodes to invert spontaneous IPSPs and make them readily visible. In nine CA1 cells the rate and amplitude of spontaneous IPSPs transiently increased but then decreased in conjunction with evoked IPSP depression. Possible KA effects on postsynaptic GABA responses were investigated by applying GABA locally to cells. KA did not significantly affect GABA responses. Prolonged exposure of CA1 cells to KA in doses of 1 microM or higher depressed intracellularly and extracellularly recorded EPSPs and all field potential activity. This depression was not apparently due to depolarization block in CA1, however. We conclude that KA induces epileptiform activity in hippocampus principally by a presynaptic block of IPSP pathways.